Prostaglandin e primary alcohols

ABSTRACT

THIS INVENTION IS A CLASS OF NEW ORGANIC COMPOUNDS STRUCTUALLY RELATED TO THE PROSTAGLANDINS. THESE COMPOUNDS HAVE THE FORMULA:   2-(HO-CH2-(CH2)N-Y-CH2-),3-(CH3-(CH2)M-Z-CH2-CH(-OH)-X-),   4-(HO-)CYCLOPENTAN-1-ONE   WHEREIN X IS -CH2CH2-OR TRANS-CH=CH- AND BOTH Y AND Z ARE -CH2CH2-, OR WHEREIN X IS TRANSCH=CH-, Y IS CIS-CH=CH-, AND Z IS-CH2CH2OR CIS CH=CH-, WHEREIN M IS 0, 1, OR 2 AND WHEREIN N IS 2, 3, 4, OR 5, AND THE TRICARBOXYACLATES THEREOF. THESE COMPOUNDS HAVE BIOLOGICAL PROPERTIES WHICH CAUSE THEM TO BE USEFUL IN THE STUDY AND TREATMENT OF PHYSIOLOGICAL CONDITIONS INVOLVING ABNORMAL LIPID MOBILIZATION AND BLOOD PLATELET AGGREGATION. THIS INVENTION ALSO INVOLVES PROCESSES AND INTERMEDIATES FOR PREPARING THESE COMPOUNDS FROM THE NATURAL PROSTAGLANDINS AND ANALOGUES THEREOF.

United States Patent 3,636,120 PROSTAGLANDIN E PRIMARYALCOHOLS John E. Pike, Kalamazoo, Mich., assignor to The Upjohn Company, Kalamazoo, Mich. No Drawing. Filed Oct. 9, 1967, Ser. No. 673,979 Int. Cl. C07c 49/28, 49/40 US. Cl. 260-586 R 6 Claims ABSTRACT OF THE DISCLOSURE This invention is a class of new orgam'c compounds structually related to the prostaglandins. These compounds have the formula:

DESCRIPTION OF THE INVENTION This invention relates to novel compositions of matter, to novel methods for producing them, and to novel chemical intermediates useful in those methods. In particular,

this invention relates to novel compounds of the formula:

0 II E --CH2 Y (CH2)m CH3OH \/!-Xlo-CH z(CH2)...CH3

: 121 H on 110 wherein X is CH CH or trans-CH:CH- and both Y and Z are CH CH or wherein X is trans- CH=C'H, Y is cis-CH=CH, and Z is CH CH or cis-CH=CH, wherein m is 0, 1, or 2, and wherein n is 2, 3, 4, or 5, and the tricarboxyacylates thereof.

The novel Formula I compounds of this invention are potent antagonists of epinephrine-induced mobilization of free fatty acids. According to Carlson et al., Inhibition of Lipid Mobilization, chapter 57, pages 557-574, in Handbook of Physiology, Waverly Press, Baltimore, Md. (1965) at page 574, Inhibition of lipid mobilization occurs normally in the intact organism due to interplay of nutritional, hormonal and nervous factors. In certain diseases, e.g., vascular diseases, diabetes mellitus, and hyperthyroidism, abnormal lipid mobilization occurs and the free fatty acid content of body fluid increases. Therefore, the novel compounds of this invention are useful in experimental medicine for both in vitro and in vivo studies intended to lead to the understanding, prevention, symptom alleviation, and cure of diseases involving abnormal lipid mobilizaton.

The novel Formula I compounds of this invention also are highly active in inhibiting blood platelet aggregation and thrombus formation induced by various biochemical stimuli, including collagen, ADP, and thrombin, and in causing thrombi to disaggregate, both in vitro and in vivo. For this reason, the novel Formula I compounds are useful in experimental medicine for both in vivo and in vitro studies intended to lead to an understanding of thrombogenesis, and the successful treatment or prevention of such physiological conditions as myocardial infarcts, post-operative venous thromboemblism, and atherosclerosis.

For the above purposes, the novel Formula I compounds are especially useful for in vivo animal studies because they are surprisingly and unexpectedly free of side effects such as blood pressure lowering and smooth muscle stimulation exhibited by other known lipid mobilization inhibitors and platelet aggregation-inhibitors. See, for eX- ample, Emmons et al., British Medical Journal, 2, 468 (1967). Thus the response of the laboratory animal to these novel compounds will not be masked, altered, or influenced by these other physiological responses.

The novel Formula I compounds of this invention are also useful in mammals, including man, as nasal decongestants. For this purpose, the compounds are used in a dose range about 10 ,ug to about 10 mg. per ml. of a pharmacologically suitable liquid vehicle or as an aerosol spray, both for topical application.

For the above purposes, the novel Formula I compounds of this invention can be used in the trihydroxy form or in the form of the corresponding tricarboxylates, preferably in the form of the tri-lower-alkanoate.

The novel Formula I compounds are produced by the following sequence of reactions:

In the above reaction scheme, X, Y, Z, m, and n are as defined above. R is hydrogen or alkyl of 1 to 8 carbon atoms, inclusive. Q is defined as any group of atoms transformable together with the attached nitrogen to carbonyl oxygen by reaction with nitrous acid.

The initial reactants of Formula II are known in the art or can be prepared by methods known in the art. In Formula II, when R is hydrogen, in is 1, and n is 3, the carbon skeleton of prostanoic acid is described. See Horton, Experientia, 21, 113 (1965) and Samuelsson, Angew. Chem. Inter. Ed. Eng. 4, 410 (1965). When R is hydrogen, m is 1, n is 3, and X, Y, and Z are each Formula II describes dihydroprostaglandin E (dihydroprostaglandin E (dihydro-PGEQ. Similarly, with the same limitations on R in and n, and the other permissible variations in X, Y, and Z, Formula II describes the other known prostaglandin E compounds, PGE PGE and PGE For a discussion of the stereochemistry of these compounds which also applies to the other compounds encompassed by Formulas I, III, and IV, see Nature, 212, 38 (1966) and footnote (3) in I. Am. Chem. Soc. 88, 3133 (1966).

The compounds within the scope of Formula II wherein R is hydrogen and m and n are other than the abovementioned combination of l and 3, respectively, are prepared by incubation of the appropriate unsaturated carboxylic acid with the enzymes of sheep seminal vesicular glands as described in U.S. Pat. No. 3,296,091.

The compounds within the scope of Formula II wherein R is alkyl of 1 to 8 carbon atoms, inclusive, are prepared by esterification of the corresponding free acid, i.e., R is hydrogen, with the appropriate diazoalkane. See, for example, US. Pat. No. 3,069,322 and British specification 1,040,544.

The transformation of the initial reactants of Formula II to the final desired primary alcohols of Formula I proceeds through two novel intermediates, compounds of Formulas III and IV. It will be observed that the overall transformation of II to I involves transformation of the -COOR moiety of the initial Formula II reactant to the CH OH moiety of the final Formula I product. The remainder of the molecule of Formula II reactant, including its stereochemical configuration, remains unchanged in the Formula I product.

Several known reagents are available for the transformation of a COOI-I or COOalkyl moiety to a -CII OH moiety. Examples are lithium aluminum hydride, lithium borohydride, and diisobutyl aluminum hydn'de. However, those reagents also will usually reduce an isolated carbonyl group to a secondary alcohol group. Such a carbonyl group is present in the cyclopentane ring of the Formula II reactant. Therefore that group must 'be protected with a group of atoms unreactive with the abovementioned carboxylate reducing agents. Of equal importance is that the protective atom grouping must be such that it can be transformed back to the carbonyl group after the carboxylate reduction without alteration of the rest of the molecule.

It is well known that reactants of Formula II are extraordinarily sensitive to acidic and basic conditions, being easily transformed thereby to other compounds. It was quite surprising and unexpected therefore that nitrous acid, especially in the absence of strong acids, for example, the mineral acids, has no substantial chemical effect on reactants of Formula II. In view of that discovery, the isolated carbonyl group of the Formula II reactant is advantageously protected with a group of atoms which can be transformed back to the carbonyl group by reaction with nitrous acid after the carboxylate reduction.

Reagents which will transform an isolated carbonyl group to another group transformable back to the carbonyl group by reaction with nitrous acid are well known 4 to those skilled in this art. Examples are hydroxylamine, alkoxyamines of the formula R ONH wherein R is alkyl of 1 to 4 carbon atoms, inclusive, semicarbazide, and thiosemicarbazide. Thereby, oximes, alkoxyoximes, semicarbazones, and thiosemicarbazones are formed.

The transformations of initial reactant II to first intermediate III, and of first intermediate III to second intermediate IV are carried out by methods known in the art for protecting isolated carbonyl groups and for reducing carboxyl groups or carbalkoxy groups. The transformation of second intermediate IV to final product II is carried out by mixing intermediate IV with nitrous acid in the range about 10 C. to about 50 C. preferably about 10 C. to about 35 C. The nitrous acid is advantageously generated in the presence of the Formula IV intermediate by dissolving or suspending the latter in a liquid alkanoic acid, e.g., acetic or propionic acid, preferably in the presence of a small amount of water, i.e., about 5 to about 25% water, and then adding an aqueous solution of an alkali metal or alkaline earth metal nitrite. At least one equivalent of the nitrite per equivalent of intermediate IV should be used, and it is usually advantageous to use about 2 to about 20 times the theoretical amount of nitrite. The resulting reaction mixture is maintained within the specified temperature range until thin layer chromatography of an aliquot shows intermediate IV has disappeared. The desired Formula I product is then isolated from the extract by methods known in the art. One useful procedure is dilution of the reaction mixture with water, and then extraction with a water-immiscible solvent, e.g., ethyl acetate. Evaporation of the extract then gives the desired product which can advantageously be purified by methods known to be useful for purifica tion of the prostaglandins, especially preparative thin layer chromatography. See, for example, Green et al., J. Lipid Research, 5, 117 (1964).

Carboxyacylation of the three hydroxy groups in the novel Formula I compounds of this invention is accomplished by interaction of the hydroxy compound with a carboxyacylating agent, preferably a carboxylic acid anhydride, for example, the anhydrides of alkanoic, cycloalkanoic, alkenoic, cycloalkenoic, aralkanoic, aromatic, and heterocyclic carboxylic acids. For example, use of acetic anhydride gives the corresponding triacetate. Similar use of propionic anhydride, butyric anhydride, isobutyric anhydride, acrylic anhydride, crotonic anhydride, cyclohexanecarboxylic anhydride, benzoic anhydride, naphthoic anhydride, p-chlorophenoxyacetic anhydride, and furoic anhydride gives the corresponding tricarboxyacylates.

The carboxyacylation is advantageously carried out by mixing the hydroxy compound and the acid anhydride preferably in the presence of a tertiary amine such as pyridine or triethylamine. A substantial excess of the anhydride should be used, preferably about 10 to about 10,000 moles of anhydride per mole of the hydroxy compound reactant. The excess anhydride serves as a reaction diluent and solvent. An inert organic diluent, for example, dioxane can be added. It is preferred to use enough of the tertiary amine to neutralize the carboxylic acid produced by the reaction.

The carboxyacylati-on reaction is preferably carried out in the range about 0 to about C. The necessary reaction time will depend on such factors as the reaction temperature and the nature of the anhydride and tertiary can be purified by conventional methods, preferably by chromatography.

The invention can be more fully understood by the following examples.

EXAMPLE 1 Oxime of 7-[3a-hydroxy-2B-(3a-hydroxy-trans-l-octenyl)--oxo-1a-cyclopentyl]heptanoic acid (PGE A solution of 0.2 g. of hydroxylamine hydrochloride and 0.25 g. of sodium acetate in 4 ml. of 1:1 aqueous methanol was added to a solution of 0.2 g. of PGE, in 2 m1. of methanol, and the mixture was allowed to stand at 25 C. for 18 hrs. At the end of this time, the methanol was removed at room temperature under a nitrogen stream. The residual mixture was diluted with water. The crystalline solid which formed was collected by filtration, washed with water, and then dried in vacuo to give 0.19 g. of solid. That solid was recrystallized from aqueous methanol to give 0.15 g. of the oxime of PGE M.P. 122124 C. On TLC, the oxime was less polar than PGE with solvent system A IX (5:5 :70 acetic acid: methanol: chloroform).

Analysis.Calcd. for C H O N (percent): C, 65,01; H, 9.55; N, 3.79. Found (percent): C, 64.87; H, 9.68; N, 3.74.

I.R.: (Principal bands; Nujol mull) 3420, 3340, 3080, 3030, 2750, 2680, 2560, 1715, 1665, 1255, 1240, 1230, 1065 and 945 cm.

Following the procedure of Example 1, the oximes of each of the following compounds were prepared:

Following the procedure of Example 1 but substituting for hydroxylamine hydrochloride, a stoichiometrically equivalent amount of methoxyamine hydrochloride, semicarbazide hydrochloride, or thiosemicanbazide hydrochloride, PGE methoxime, PGE semicarbazone, and -PGE thiosemicarbazone were prepared. Similarly, substituting for PGE the prostaglandins and analogs thereof named following Example 1, and substituting for hydroxylamine hydrochloride the stoichiometrically equivalent amount of methoxylamine hydrochloride, semicarbazide hydrochloride, or thiosemicarbazide hydrochloride, following the procedure of Example 1, the corresponding derivative of the named prostaglandins and analogs there of were prepared.

EXAMPLE 2 Oxime of methyl 7-[3u-hydroxy-2 3-(3a-hydroxyoctyl)- 5 oxo 1a cyclopentyl]heptanoate (dihydro-PGE methyl ester) A mixture of 25 mg. of dihydro-PGE methyl ester, 1 ml. of methanol, 25 mg. of hydroxylamine hydrochloride, 30 mg. of sodium acetate and 0.5 ml. of water was allowed to stand about 18 hrs. at 25 C. The reaction mixture was concentrated at 25 C. under a stream of nitrogen. An oil separated in the residual mixture, and was extracted with dichloromethane. The dichloromethane ex tract was washed with water, dried, and evaporated to give an oily residue. That residue was dissolved in a small amount of a mixture of 50% ethyl acetate and 50% cyclohexane, and the solution was chromatographed on 15 g. of silica gel. Elution with a mixture of 75% ethyl acetate and 25% cyclohexane and evaporation of the eluate gave 24 mg. of the oxime of dihydro-PGE methyl 6 ester. On TLC analysis (silica gel; ethyl acetate), one spot was obtained; slightly more polar than dihydro-PGE methyl ester with the same solvent system.

LR. (principal bands, dichloromethane, solution): 3300, 1745 and 930 cm.

EXAMPLE 3 Oxime of methyl 7-[3u-hydroxy-2fl-(3a-hydroXy-trans- 1 octenyl) 5-oxo-la-cyclopentyl]-cis-5-heptenoate oxime (PGE methyl ester) A solution of 25 mg. of PGE methyl ester in 1 ml. of methanol was mixed with a solution of 25 mg. of hydroxylamine hydrochloride and 30 mg. of sodium acetate in 0.5 m1. of water. The mixture was allowed to stand at 25 C. for about 18 hrs. Then, the mixture was concentrated by evaporation under a stream of nitrogen to remove the methanol. The residue was diluted with water and extracted with dichloromethane. The extract was washed with water, dried over magnesium sulfate, and evaporated to give a residue. That residue was purified by chromatography over g. of silica gel, eluting first with a mixture of 50% ethyl acetate and 50% cyclohexane, and next with a mixture of 75 ethyl acetate and 25% cyclohexane. The eluate fractions were evaporated to give the oxime of PGE methyl ester.

Following the procedure of Example 3, oximes of the following were prepared:

( 1) methyl 7 [3a-hydroxy-2fl-(3a-hydroxy-trans-1-cis- 5 octadienyl) 5 oxo-la-cyclopentyl]-cis-5-heptenoate (PGE methyl ester),

(2) methyl 6 [3a hydroxy-2B-(3u-hydroxy-trans-1- octenyl) 5 oxo Ia-cyclopentyl]hexanoate,

(3) methyl 6 [3a hydroxy-2,8-(3ot-hydroxy-trans-1- octenyl -5-oxo- 1 a-cyclopentyl] -cis-4-hexeno ate,

(4) methyl 8 [30 hydroxy 2,8 (3u-hydroxy-trans-1- octenyl)-5-oxo-1a-cyclopentyl]-cis-6-octenoate,

(5) ethyl 6 [3a. hydroxy 2B-(3a hydroxy-trans-lheptenyl -5-oxo-1a-cyclopentyl] hexanoate.

EXAMPLE 4 Methoxine of methyl 7[3a-hydroxy 25 (3a-hydroxyoctyl)-5-oxo lu-cyclopentyl]heptanoate (dihydro-PGE methyl ester) A mixture of 25 mg. of dihydro-PGE methyl ester, 25 mg. of methoxamine hydrochloride and 1 ml. of pyridine was allowed to stand 18 hrs. at 25 C. under nitrogen. The resulting mixture was poured into about 20 ml. of water, and then extracted with dichloromethane. The extract was washed with water, dried over sodium sulfate, and evaporated under reduced pressure to give a residue, which was chromatographed on silica gel as described in Example 2 to give the methoxime of dihydro-PGE methyl ester.

Following the procedure of Example 4, methoxime of the following were prepared:

(1) PGE methyl ester,

(2) PGE methyl ester,

(3) PGE methyl ester,

(4) methyl 6-[3oc hydroxy 2p-(3a-hydroxy-trans-1- octenyl)-5-oxo-1a-cyclopentyl]hexanoate,

(5) methyl 6 [30c hydroxy-2,8-(3a-hydroxy-trans-1- octenyl)-5-oxo-1a-cyclopentyl]-cis-4-hexenoate,

(6) methyl 8 [3a hydroxy-2 8-(3a-hydroxy-trans-1- octenyl -5-oxo-1a-cyclopentyl]-cis-6-octenoate,

(7) ethyl 6 [3a hydroxy 2,6 (3a-hydroxytrans-1- he ptenyl -5 -oxo- 1 u-cyclopentyl hexanoate.

EXAMPLE 5 Semicarbazone of methyl 7 [30c hydroxy-2fi-(3a-hydroxyoctyl) 5 oxo 1u-cyclopentyl]heptanoate-(dihydro-PGE methyl ester) A solution of mg. of dihydro-PGE methyl ester in 1 m1. of methanol was mixed with a solution of 35 mg. of semicarbazide hydrochloride and mg. of sodium (1) PGE methyl ester,

( 2) PGE methyl ester,

(3) PGE methyl ester,

(4) methyl 6-[3a-hydroxy-2fi(3a-hydroxy-trans-loctenyl 5-oxo-1a-cyclopentyflhexanoate,

(5 methyl 6 3u-hydroxy-2fi-( 3 whydroxy-trans- 1- octenyl -5-oxo- 1 a-cyclopentyl] -cis-4-hexanoate,

(6) methyl 8-[3ix-hydroxy-2fi-(3ot-hydroxy-trans-1- octenyl -5-oxo- 1 u-cyclopentyl] -cis-6-octenoate,

(7) ethyl 6-[3a-hydroxy-2;3-(3a-hydroxy-trans-1- heptenyl) -5-oXo-1a-cycl0pentyl] hexanoate.

Following the procedure of Example 5 but substituting thiosemicarbazide hydrochloride for semicarbazide hydrochloride, thiosemicarbazones of the following were prepared:

(1) dihydro-PGE methyl ester, (2) PGE; methyl ester, (3) PGE methyl ester, (4) PGE methyl ester.

EXAMPLE 6 Oxime of 4a-hydroxy-2ot-( 7-hydroxyheptyl -3;3- 3 0L- hydroxy-trans-l -octenyl) cyclopentanone A solution of 250 mg. of the oxime of PGE in 17 ml. of dry tetrahydrofuran was added with stirring to a suspension of 1.2 g. of lithium aluminum hydride in 119 ml. of dry diethyl ether under nitrogen. The mixture was stirred for 2 hrs. at 25 C. Then, excess lithium aluminum hydride was decomposed by successive additions of ml. of ethyl acetate and water. The resulting mixture was filtered and the organic layer was separated, washed with water, dried over sodium sulfate, and evaporated under reduced pressure to give a crystalline residue which was triturated with diethyl ether. The diethyl ether solution was evaporated to dryness, and the residue was crystallized from a mixture of ethyl acetate and a mixture of isomeric hexanes (Skellysolve B) to give mg. of the oxime of 4a-hydroxy-2u-(7-hydroxyheptyl) 3p (3a hydroxytrans-l-octenyl)cyclopentanoneg M.P. 118-124 C.

Analysis.Calcd. for C H O N (percent): C, 67.57; H, 10.49; N, 3.74. Found (percent): C, 66.83; H, 10.44; N, 3.40.

I.R.: (Principal bands, Nujol mull) 3280, 1670, 1125, 1085, 1050, 1030, 1000, 975, and 955 cm- TLC: More polar than the oxime of PGE on the A IX solvent system.

EXAMPLE 7 The oxime of 4m-hydroxy-2u-(7-hydroxyheptyl)-3{3- (3 :x-hydroxyoctyl) cyclopentanone A solution of 250 mg. of the oxime of dihydro-PGE methyl ester in 15 ml. of dry tetrahydrofuran was added with stirring to a suspension of 1.2 g. of lithium alumi- 65 num hydride in 120 ml. of dry diethyl ether under nitrogen. The mixture was stirred for about 2 hrs. at 25 C. Then, the excess lithium aluminum hydride was decomposed by additions of 50 ml. of ethyl acetate and then water. The resulting mixture was filtered and the organic layer was separated, washed with water, dried over sodium sulfate, and evaporated under reduced pressure to give the oxime of 4a-hydroxy-2u-('7-hydroxyheptyl)- 3B (3a hydroxyoctyl)cyclopentanone. This product is further purified by chromatography over silica gel using mixtures of ethyl acetate and cyclohexane containing increasing amounts of ethyl acetate for elution.

Following the procedures of Examples 6 or 7 but substituting for the oxime of PGE or the oxime of dihydro- PGE; methyl ester, the following:

dihydro-PGE oxime;

PGE methyl ester, oxime;

PGE methyl ester, oxime; PGE oxime;

PGE methyl ester, oxime; PGE oxime;

methyl 6- 3a-hydroxy-2fi- 3 ot-hydroxy-trans-l-octenyl) 5-oxo-la-cyclopentyl]hexanoate, oxime; 6- [3a-hydroxy-2 3-(3a-hydroxy-trans-1-octenyl) -5-oxolot-cyclopentyflhexanoic acid, oxime;

methyl 6- [3 u-hydrOxY-Zfl- 3 oc-hYdIOXY-tl'flIlS- l-octenyl) 5-oxo-1a-cyclopentyl]-cis-4-hexenoate, oxime;

6- [3 a-hydr0xy-2/3- 3ot-hydroxy-transl-octenyl) -5-oxolet-cyclopentyl]-cis-4-hexenoic acid, oxime;

methyl 8- 3 u-hydroxy-2B- (3 u-hyd roxy-trans-l-octenyl) 5-oxo-1a-cyclopentyl]-cis-6-octenoate, oxime;

8- 3 a-hydroXY-ZB- 3 u-hydroxy-trans- 1-octenyl)-5oxo- 1ot-cyclopentyl]-cis-6-octen0ic acid, oxime;

ethyl 6- 3 ot-hYdIOXY-Zfi- 3 a-hydroxy-transl-heptenyl) 5-oxo-1u-cyclopentynhexanoate, oxime;

6- 3ot-hydroxy-2B- 3a-hydroxy-transl-heptenyl -5- oxo- 1 a-cyclopentyl] hexanoic acid, oxime;

there were obtained:

( 1 4zx-hYdIOXY-2a- 7-hydroxyheptyl -3,6- 3 a-hydroxyoctyl)cyclopentanone, oxime;

( 2 4a-hyd roxy-Za- 7-hydroxyheptyl) -3 [3-( 3 a-hydroxytrans-l-octenyl cyclopentanone, oxime;

( 3 4OL-hydl'OXY-2 a- (7-hydroxy-eis-2-heptenyl -313-( 3ahydroxy-transl-oetenyl) cyclopentanone, oxime;

(4) 4a-hydroxy-2a- 7-hydroxy-cis-2-heptenyl -3;8- 3 GL- hydroxy-trans- 1-cis-5-octadienyl cyclopentanone, oxime;

(5 4ot-hydroxy-2 a- 6 -hyd roxyhexyl -3 ,6-( 3 ot-hydrox ytrans-l-octenyl) cyclopentanone, oxime;

( 6) 4a-hYdIOXY-2ot- 6-hydroxy-cis-4-hexenyl) -3fl- 3ahydroxy-trans-l-octenyl) cyclopentanone, oxime;

( 7) 4zx-hYdIOXY-Ztx- 8-hydroxy-cis-6-octenyl) -3,-( 30- hydroxy-transl -octenyl cyclopentanone, oxime;

( 8 4a-hydroxy-2 oz- 6-hydroxyhexyl) -3 ;3( 3u-hydroxytransl-heptenyl) cyclopentanone, oxime.

Following the procedure of Example 7 but substituting for the oxime of dihydro PGE methyl ester, the methoximes, semicarbazones and thiosemicarbazones of:

(1) dihydro-PGE methyl ester; dihydro PGE 2) PGE methyl ester; PGE 3) PGE methyl ester; PGE 4) PGE methyl ester; PGE

4a-hydroxy-2a- 7-hydroxyheptyl) -3,6- (3 a-hydroxyoctyl)-cyclopentanone, methoxime; 4OL-hydI'OXy-2OL- (7-hyclroxyhep tyl) 3 ,6- (3 a-hydroxyoctyl)-cyclopentanone, semicarbazone; and 4a-hydroxy-2a.- (7-hydroxyheptyl) -3(3- (3 a-hydroxyoctyl)-cyclopentanone, thiosemicarbazone;

4a-hydroxy-2a- (7-hydroxyheptyl)-3fi- (3 tX-hydl'OXytrans-l-octenyl)cyclopentanone, methoxime;

4a-hydroxy-2 a- 7-hydroxyheptyl -3 B- 3 ot-hydroxytrans-l-octenyl)cyclopentanone, semicarbazone; and

4a.-hydroxy-2a- (7-hydroxyhepty1 -3 ,8- 3 whYdI'OXY- trans-l-octenyl)cyclopentanone, thiosemicarbazone;

4a-hydroxy-2a- (7 -hydroxy-cis-2-heptenyl) -3,B (3 u-hydroxy-transl-octenyl) cyclopentanone, methoxime; 1 5

4a-hydroxy-2a- 7-hydroxy-cis-2-heptenyl) -3 ,8- (3 a-hydroxy-trans-l-octenyl)cyclopentanone, semicarbazone; and 4a-hYdIOXY-2ot- (7-hydroxy-cis-2-heptenyl) -3fl- (3 ochydroxy-trans-l -octenyl cyclopentanone, thiosemicarbazone;

EXAMPLE 8 4oz-hYdI'0XY-2ot- (7-hydroxyheptyl -3 {3- 3 OL-hydI'OXytransl-octenyl) cyclopentanone A solution of 146 mg. of the oxime of 4a-hydroxy-2a- (7 hydroxyphenyl) 3,8-(3a-hydroxy-trans-l-octenyl)- cyclopentanone in 10 ml. of 90% aqueous acetic acid was cooled to 10 C., and 5 ml. of a 10% aqueous solution of sodium nitrite was added. The mixture was allowed to stand 1 hr. at 10 C. Then the mixture was allowed to warm to room temperature and treated with an additional 5 ml. of 10% aqueous sodium nitrite. The mixture was allowed to stand min. at 25 C. Excess water was then added, and the mixture was extracted with ethyl acetate. The organic extracts were separated, combined, washed with aqueous sodium bicarbonate and then with water, and dried over sodium sulfate. Evaporation of the solvent gave 163 mg. of a residue comprising 4a-hydroxy- 2oz (7-hydroxyheptyl -3 {3- 3 a-hydroxy-trans-1-0ctenyl)- cyclopentanone. The residue was dissolved in 1:1 ethyl acetatezcyclohexane and chromatographed over a column of 20 g. of acid-washed silica gel made up in 1:1 ethyl acetatezcyclohexane. The column was eluted successively with 1:1 ethyl acetatezcyclohexane, ethyl acetate, 2% methanol in ethyl acetate, and 5% ethanol in ethyl acetate. Evaporation of the eluate gave 67 mg. of crystalline fractions. This material was recrystallized from ethyl acetate to give hydroxy 2a.-(7-hydroxyheptyl)-3fi-(3a-hydroxy trans 1 octenyl)cyclopentanone; MP. 106 108 C.

Analysis.Calcd. for C H O (percent): C, 70.54; H, 10.66. Found (percent): C, 70.35; H, 11.08.

I.R.: (principal bands, Nujol mull) 3470, 3360, 1725, 1160, 1125, 1080, 1055, 1020, 990, 975 and 970 cm."

TLC: More polar than the parent oxime on the A IX solvent system.

*Following the procedure of Example 8 but substituting for 4a hydroxy-2a-(7-hydroxyheptyly)-3fi-(3a-hydroxytrans-l-octenyl)-cyclopentanone, oxime, the following:

1 4a-hdroxy-2a- (7 -hydroxyheptyl) -3 8- 3 tat-hydroxyoctyl) cyclopentanone, oxime; (2) 4OL-hydI'OXy-20L- (7-hydroxy-cis-2-heptenyl) -3{3- (3 a-hYClIOXY-UfiHS- l-octenyl cyclopentanone, oxime;

(3) 4a-hydroxy-2a-( 7-hydroxy-cis-2-heptenyl)-3B-( 3ahydroxy-trans-l-cis-S-octadienyl)cyclopentanone, oxime;

(4 4a-hydroxy-2a- 6-hydroxyhexyl -3 18- 3 a-hydroxy trans-l-octenyl)cyclopentanone, oxime;

(5 4a-hydroxy-2a- 6-hydroxy-cis-4-hexenyl -3 [i- 3 ahydroxy-trans-l-octenyl cyclopentanone, oxime;

(6) 4a-hydroxy-2a- 8-hydroxy-cis-6-octenyl -3fl- 3ozhydroxy-trans-l-octenyl cyclopentanone, oxime;

( 7) 4zx-hYdI'OXY-2u- (6-hdroxyhexyl)-3fl- (3 a-hydroxytrans-l-heptenyl)cyclopentanone, oxime;

there were obtained:

( 1 4a-hydroxy-2u-(7-hydroxyheptyl) -3B- (3 a-hydroxyoctyl cyclopentanone;

(2) 4a-hydIOXY-2u- 7-hydroxy-cis-2-heptenyl -3 ,8- 3 ahydroxy-transl-octenyl cyclopentanone;

(3 4a.-hydroxy-2a- 7-hydroxy-cis-2-heptenyl -3 8- 3 ahydroxy-transl-cis-S-octadienyl) cyclopentanone;

(4) 4a-hydroxy-2a- 6-hydroxyhexyl) -3 [3- 3a-hydroxytransl-octenyl cyclopentanone;

( 5 4a-hydroxy-2a- (6-hydroxy-cis-4-hexenyl) -3fl- (3 ahydroxy-transl-octenyl cyclopentanone;

(6 4a-hydroxy-2 a- 8-hydroxy-cis-6-octenyl -3fl- 3 ahydroxy-transl-octenyl cyclopentanone;

(7) 4 a-hydroxy-2m- 6-hydroxyhexyl) -3 ,8- (3 u-hydroxytrans-1-heptenyl)cyclopentanone.

The above products were also obtained by following the procedures of Example 8 but replacing the starting oximes with the corresponding methoximes, semicarbazones, and thiosemicarbazones.

I claim:

1. A compound of the formula:

.HHoH no wherein X is -CH CH- or trans-CH=CH- and both Y and Z are CH CH or wherein X is trans- CH=CH, Y is cis-CH=CH, and Z is CH C H or cis-CH=CH, wherein m is 0, 1 or 2, and wherein m is 2, 3, 4, or 5,

2. A compound of the formula:

wherein X is CH CH or trans-CH=CH-- and both Y and Z are CH CH or wherein X is trans- CH=CH, Y is cis-CH=CH, and Z is -CH CH or cis-CH=CH.

3. A compound according to claim 2 wherein X, Y, and Z are CH2C'H2'.

4. A compound according to claim 2 wherein X is trans- CH=CH, Y is cis-CH =CH, and Z is CH CH 5. A compound according to claim 2 wherein X is trans- CH=CH, and Y and Z are cis-CH=CH.

6. A compound of the formula:

(References on following page) 11 12 References Cited Kirk et aL: Encyclopedia of Chemical Technology, UNITED STATES PATENTS 3,290,226 12/1966 Beal et a1. 260514 101 [1965] OTHER REFERENCES BERNARD HELFIN, Primary Examiner Morrison et a1.: Organic Chemistry, pp, 460, 461 and N. P. MORGENSIERN, Assistant Examiner Noller: Chemistry of Organic Compounds, third edition, 1). 256 [I965]. 10 260-468 R, 514 R, 552. SC, 554, 566 A, 566 AB, 999

Bergstrom et aL: Ann. Rev. of Biochem, vol. 39, p. 

